Collagen is a protein which is widely used in medical field as a biomaterial for restoring the body damage and as a carrier of various drugs. The collagens currently used for such applications are collagens of animal origin extracted from the tissue of cows, pigs, and the like. Use of a collagen of human origin is desirable in consideration of immunological reactions, and also, contamination of pathogens such as viruses and prions from animal tissues which is currently a serious issue. In view of such situation, the inventors of the present invention have proposed a method for producing a recombinant human collagen having a triple helical structure equivalent to the one found in human body by infecting insect cells with a recombinant virus having the cDNA coding for a human collagen inserted therein (JP-A 8-23979). This method is also described in Tomita et al., (Biochemical J. 312, 847-853 (1995) and J. Biochem. 121, 1061-1069 (1997)). And the similar methods are described in Lamberg et al., (J. Biol. Chem. 271, 11988-11995 (1996)), Myllyharju et al., (J. Biol. Chem. 272, 21824-21830 (1997)), Nokelainen et al., (Matrix Biology, 16, 329-338 (1998)).
Prockop et al. have also proposed a method for producing recombinant human collagens by using mammal cells or yeasts (JP-A 7-501939, Published Japanese Translation of WO93/07889). Ala-Kokko et al., (J. Biol. Chem. 266, 14175-14178 (1991)), Geddis et al., (Matrix 13, 399-405 (1993)) and Fertala et al., (Biochemical, J. 298, 31-37 (1994)) disclose the similar methods.
It is not clear whether a plurality of proteins having formed as fusion protein can always exhibit their own activities, because the activity of a protein is dependent on its conformation. Further, it is not clear whether a trimer of the fusion protein can be formed which retains the activities of the collagen and the peptide, because trimeric fusion protein containing essentially full length of collagen has not been heretofore reported.
On the other hand, cell growth factors, cytokines and various other biologically active peptides are highly hoped for use as a drug. These peptides, however, suffer from high elimination rate, and practical use of such biologically active peptides is often prevented by their high elimination rate. In order to obviate such situation, mixing of the biologically active peptide with the collagen and embedding of the mixture in the body for controlled release has been proposed (Fujioka et al., J. Controlled Release 33, 307 to 315, 1995). This reference describes that when interferon (INF) was mixed with gelatin or collagen and embedded in animal body the INF release from gelatin gel was 100% after 1 day, but the release from collagen gel was less than 100% though more than 60% after 1 day. It also describes that drying of the mixture of INF and collagen reduces the release rate of INF.